1. Field of the Invention
The present invention relates to a pharmaceutical composition comprising a bisphosphonate or a pharmaceutically acceptable salt thereof for preventing or treating diabetes mellitus (more specifically, type II diabetes) and a method comprising single or multiple administration of the pharmaceutical composition to a patient for preventing or treating diabetes mellitus.
2. Description of the Related Art
Bisphosphonates are used widely to inhibit the activity of osteoclasts accompanying excessive or inappropriate bone resorption when treating various benign or malignant diseases. The bisphosphonates, so called pyrophosphate analogs because they are similar in structure to pyrophosphate, reduce the incidence of skeletal related problems (skeletal related events), provide a clinical benefit to patients, and improve survival rate of patients. It has been reported that the bisphosphonates may prevent bone resorption in vivo, and treat osteoporosis, osteopenia, Paget's disease, tumor-induced hypercalcemia (TIH), bone metastasis and multiple myeloma(MM) (reference: Fleisch H 1997 Bisphosphonates clinical. Bisphosphonates in Bone Disease. From the Laboratory to the Patient. Eds: The Parthenon Publishing Group, N.Y./London, pages 68-163). It is identified that the bone resorption inhibition mechanism of bisphosphonates is based on the bisphosphonates' strong coupling with hydroxyapatite crystal of bones, reduction of bone metabolic circulation, reduction of blood hydroxyproline or alkaline phosphatase levels, and inhibition of osteoclasts' formation, supplementation, and activation.
The only commercially used-medicine for bone disease (bone metastasis of breast cancer and osteoporosis) is zoledronic acid of Novartis [Zomera, Aclasta or Reclast]. The zoledronic acid is a chemical of bisphosphonates group, a transformed form of pyrophosphate which was used to prevent corrosion of metal pipes etc.
Pharmacokinetically, while the pyrophosphates having a P—OP structure can be easily hydrolyzed, the bisphosphonates having a P—C—P structure cannot be easily hydrolyzed and thus it has relatively a long-term half-life. The bisphosphonates is used as a treatment for osteoporosis since it reduces bone resorption by inhibiting osteoclasts. Out of the two lateral chains (R′ and R2) binding to carbon atom of bisphosphonates, R1 can bind to calcium of bones with its hydroxide(—OH) group while modifying R2 into various forms to increase the inhibition effect of bone resorptions. Most of the bisphosphonates are structurally highly hydrophilic and the absorption rate is very low and thus they are manufactured to use as an intravenous injection dosage form. The bisphosphonates inhibit the maturation of osteoclasts and prevent bone resorption by attaching to the bone surface of bone formation is actively made. Also, the bisphosphonates inhibit the transferring of osteoclasts to the region of bone resorption and reduce the generation of cytokines stimulating the bone resorption. Beside the actions above, the bisphosphonates prevent the invasion of tumor cells and induce the apoptosis of tumor cells in the bone matrix.
The biggest emerging problem of the bisphosphonates side effects, except the known problems of stroke and atrial fibrillation, is bisphosphonates induced osteonecrosis of the jaws(BIONJ), and the exact mechanism of BIONJ is still unknown. BIONJ is a severe bone disease that affects the maxilla, the mandible and the tooth root and the definitive symptom is the exposure of mandibular or maxillary bone. In healthy bone tissues, a homeostasis is maintained by repetitive bone resorption and bone apposition. Diseased or damaged bone is resorbed through the osteoclasts mediated process and then osteoblasts form new bone to replace it, thus maintaining healthy bone density. This process is commonly called remodeling. The main pharmacological action of bisphosphonates is inhibition of the maturation of osteoclast driven bone resorption, and thus bone resorption is inhibited by bisphosphonates. The bisphosphonates prevent osteoblasts bone formation and thus bone generation is not occurred, and thereby micro-damage and fractures are cumulated. Bisphosphonates may affect to the mucous membrane of the gingiva and the tooth root to be exposed outside of the gingiva. Especially in case of frequently masticated jaw bone, the bone turnover rate of jaw is about 10 times higher than the one of normal bone, and thus it is easily affected by bisphosphonates. Also, the bisphosphonates increases the possibility of occurrence of BIONJ by blocking a sufficient blood supply through the inhibition of blood vessels by bisphosphonates.
Diabetes mellitus, or simply diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced. Type II diabetes mellitus results from a deficiency of insulin releasing from pancreas beta cells or combined with insulin resistance, a condition in which cells fail to use insulin properly. In former case, the diabetes mellitus is caused by imbalance between blood glucose homeostasis and lipid/protein metabolism due to the inhibition of phosphorylation of insulin receptor (IR). That is, if the insulin binding with IR is inhibited or dephosphorylation is induced in phosphorylation pathway, then the insulin function may be reduced.
In case of insulin resistance, cells do not respond effectively to the insulin produced by pancreas and thus insulin may be overproduced. It may progress to the state of insulin resistance and the pancreas cannot produce the amount of insulin properly, and finally blood glucose levels will rise.
PTP-1B (protein tyrosine phosphatase 1B) can block the signal transduction of insulin by stimulating dephosphorylation of IR and insulin receptor substrate (IRS). PTP-1B can control insulin sensitivity in liver and perform a unique role in insulin receptor—substrates (i.e., IRS1 and IRS2) interaction and hepatic insulin action mechanism. Recently several PTP-1B inhibitors (i.e., negative regulator of insulin signaling) suggested a treating way of type II diabetes mellitus by increasing insulin sensitivity, improving glucose tolerance and insulin function through maintaining IR phosphorylation state in clinical and non-clinical trials.